KSHV is a relatively new herpesvirus that has been linked to KS, primary effusion lymphoma (PEL), and the plasmablastic variant of Castleman's disease. Although KSHV is considered essential for development of all forms of KS, the mechanisms of how KSHV contributes to KS tumor cell growth and the elucidation of co-factors that may be involved in KS pathogenesis are poorly understood. Over the last several years, we have pursued projects that have centered on understanding the molecular mechanisms involved in reactivation (latent-to-lytic switching) of KSHV. Viral reactivation occurs prior to onset of KS lesions and is a potential target for blocking KS development. After developing a novel assay to detect and quantify viral reactivation within single cells, we studied a variety of drugs, signal transduction inhibitors, and conditions (e.g., hypoxia) that either induce or inhibit reactivation. This work has led to the identification of histone deacetylase inhibitors as a potential new class of drugs that may be clinically useful in KS patients. In addition, we have recently created transgenic mice that express purported KSHV oncogenes (v-cyclin and LANA) within lymphatic endothelial cells. To create tissue-specific expression, we first cloned, sequenced, and characterized the murine VEGFR-3 promoter, a gene specifically expressed in lymphatics. Breeding and characterization of the mice are now underway. In summary, these studies should be critical in understanding how KSHV induces the development of KS and may aid in the design of novel therapeutic approaches that target KS-specific markers. 100% AIDS-RELATED